FULL PAPER Postprint de EurJOC 2015, 4143-4152
Mechanism Switch in Mannich-type Reactions. ELF and NCI
Topological Analyses of the Reaction between Nitrones and
Lithium Enolates
David Roca-López,[a] Victor Polo,[b] Tomás Tejero,[a] and Pedro Merino*[a]
Abstract: The mechanism of the addition of lithium enolates derived
from esters, ketones and aldehydes to nitrones (Mannich-type
reaction) has been studied using DFT methods. While the reactions
with α-methoxy and α-methyl enolates takes place through a
stepwise mechanism, consisting of an initial nucleophilic attack of
the enolate to the nitrone carbon followed by a second nucleophilic
attack of the nitrone oxygen to the formed carbonyl group, the
reaction with α-unsusbtituted enolates takes place through a one-
step mechanism. The IRC analysis shows the presence of a hidden
intermediate in agreement with one kinetic step two stages process.
The topological analysis of the electronic localization function (ELF)
confirms that only when the first C-C bond is formed, does the C-O
bond formation begin. The NCI analyses, are also in agreement with
the formation of intermediates for α-methoxy and α-methyl enolates
and a highly asynchronous one-step process in the case of α-
unsusbtituted enolates.
Introduction
Mannich-type reactions are probably the most popular approach
for the synthesis of β-amino carbonyl compounds.[1] The direct
addition of enolates to a variety of functionalities including
imines[2] as well as other C=N groups such as nitrones,
hydrazones and iminium salts[3] is especially useful to create
different types of β-nitrogenated carbonyl derivatives in a single
synthetic operation. In particular, the use of nitrones as
substrates has received considerable attention because they
lead to β-aminocarbonyl functionalities in which the nitrogen
group is at an intermediate oxidation state (Scheme 1). The final
product can be a β-hydroxyamino carbonyl derivative or the
corresponding isoxazolidin-2-one obtained after an
intramolecular cyclization. In addition, the Mannich-type reaction
of nitrones has provided access to enantiomerically pure
compounds of biological and pharmacological interest including
aminosugars,[4] iminosugars,[5] nucleoside analogues,[6]
sphingosines[7] and aminoacids.[8]
Scheme 1. Mannich-type reactions of nitrones
Several nucleophiles can be used in the reaction,[9] the most
commonly employed being enolates derived from esters in the
form of lithium,[6a] sodium,[6a] boron[8b,10] and titanium salts.[8b,10-11]
Silyl enolates derived from esters (silyl ketene acetals) have also
extensively used in the presence of Lewis acids.[4b,6b,c 8c,e,12]
Recently, enol silanes formed in situ, derived from ketones,
amides and thioesters have been reported to add to nitrones in
the presence of trialkylsilyl trifluoromethane-sulfonates.[13] On
the contrary, there are only two examples regarding the reaction
between nitrones and metal enolates derived from ketones[14]
and a self-catalyzed Mannich-type reaction between nitrones
and 1,3-dicarbonyl compounds (without any base) has been
recently reported.[15] To the best of our knowledge, no previous
reports on the reaction with metal enolates derived from
aldehydes are documented.
From a mechanistic point of view, the addition of silyl ketene
acetals to nitrones presented some controversy since the
reaction was initially postulated to take place through a stepwise
mechanism[8c,16] whereas a concerted mechanism involving a
pentacoordinated silicon was also invoked on the basis of
semiempirical calculations.[8e] On the other hand, a different
semiempirical study pointed out that the mechanism of the
reaction could change from concerted to stepwise depending on
the Lewis acid used as activating agent.[17] Further DFT
calculations with very simple models in gas phase and without
considering Lewis acids (which are required for the advance of
the reaction) presented the reaction like a typical concerted
inverse-demand 1,3-dipolar cycloaddition.[18] Finally,
consideration of a more realistic scenario taking into account
both the presence of Lewis acids and solvent effects confirmed
that both concerted and stepwise mechanisms are
competitive.[19]
[a] D. Roca-López, Prof. T. Tejero and Prof. P. Merino
Laboratorio de Síntesis Asimétrica. Departamento de Síntesis y
Estructura de Biomoléculas. Instituto de Síntesis Química y Catálisis
Homogénea (ISQCH). Universidad de Zaragoza. CSIC. Campus
San Francisco. E-50009 Zaragoza. Aragón, Spain.
E-mail: [email protected]
[b] Dr. V. Polo
Departamento de Química Física and Instituto de Biocomputación y
Física de Sistemas Complejos (BIFI). Universidad de Zaragoza.
Campus San Francisco. E-50009 Zaragoza. Aragón, Spain.
Supporting information for this article is given via a link at the end of
the document.
FULL PAPER Postprint de EurJOC 2015, 4143-4152
Experimental and theoretical investigations have
demonstrated that the reactions of organometallic reagents,
such as organolithium[19-20] and Grignard[21] derivatives, with
nitrones take place through the initial formation of a complex SC
(Scheme 2). When the nucleophile is a lithium enolate (usually
derived from an ester) the final product of the reaction is an
isoxazolidine. This heterocycle could be formed from the initial
complex SC through either a concerted mechanism (Scheme 2,
A) or a typical nucleophilic addition stepwise mechanism
(Scheme 2, B). During past investigations we confirmed the
stepwise mechanism for α-methoxyenolates derived from esters
(Z=OR).[19,20c] In that case, the stepwise mechanism is favored
because of the stabilization of the developing positive charge in
TS-B1 by the Z=OR group. However, it remains unstudied the
case of lithium enolates derived from aldehydes and ketones
(Scheme 2, Z = H, R) in which such stabilization is not present
and the concerted mechanism could be an option.
Scheme 2. One-step (A) and stepwise (B) mechanisms for the addition of
lithium enolates to nitrones.
Despite the apparent similarity between lithium enolates derived
from aldehydes, ketones and esters all these species are rather
different if we consider their electronic properties,[22] which are
crucial for the stability of postulated intermediates. In order to
shed some light on the preferred pathways (concerted or
stepwise) it is necessary a full theoretical study considering in
detail all the possible paths. Herein, we report a DFT study on
the reaction of lithium enolates derived from esters, ketones
aldehydes. The study includes a detailed analysis of all points of
the intrinsic reaction coordinates (IRCs) by using NCI and ELF
topological analyses that will allow discerning the concertedness
of each process.
Computational Methods
All of the calculations were performed using the Gaussian09
program.[23] Molecular geometries were optimized with the M06-
2X functional[24] in conjunction with cc-pVTZ basis set.[25] Truhlar
and co-workers reported that for examining barrier heights, a
minimally augmented basis set like the Dunning cc-pVTZ is
appropriate.[26] It was not necessary to augment the pTZV basis
with extra diffuse functions, as tests carried out by using aug-cc-
pVTZ basis, resulted in changes in the relative energies of less
than 1 kcal/mol while making calculations considerably more
time-consuming. Moreover, the use of M06-2X in conjunction
with cc-pVTZ basis has provided excellent results in related
calculations with nitrones.[27] We can therefore expect that the
computed values should be sufficiently reliable to be able to
draw meaningful conclusions. Analytical second derivatives of
the energy were calculated to classify the nature of every
stationary point, to determine the harmonic vibrational
frequencies, and to provide zero-point vibrational energy
corrections. The thermal and entropic contributions to the free
energies were also obtained from the vibrational frequency
calculations, using the unscaled frequencies. All transition
structures were characterized by one imaginary frequency and
were confirmed to connect to reactants and products by intrinsic
reaction coordinate (IRC) calculations.[28] The IRC paths were
traced using the second order González-Schlegel integration
method.[29] Solvent effects were calculated using the continuum
solvation model (PCM)[30] using a dielectric constant of 7.4257 to
simulate THF, and microsolvation of the lithium atom was
considered by explicit inclusion of dimethyl ether ligands (to
reduce computational cost we replace discrete THF molecules
by dimethyl ether units) to complete the coordination sphere of
lithium, according to previous reports by Domingo and co-
workers.[31] A four-fold (tetrahedral) coordination sphere was
chosen for the lithium atom in agreement with previous
studies.[32] NCI (non-covalent interactions) were computed using
the methodology previously described.[33] Data were obtained
with the NCIPLOT program.[34] A density cutoff of ρ=0.1 a.u. was
applied and the pictures were created for an isosurface value of
s=0.4 and colored in the [-0.02,0.02] a.u. sign(λ2)ρ range using
VMD software.[35] The electronic structures of stationary points
were analyzed by the topological analysis of the gradient field of
electron localization function (ELF)[36] developed by Silvi and
Savin.[37] The ELF study was performed with the TopMod
program[38] using the corresponding monodeterminantal
wavefunctions of the all structures of the IRC. The topological
analysis of the gradient field of ELF has showed to be a powerful
tool for the study of the bonding changes along an organic
reaction.[39] Advantages and drawbacks of NCI index, compared
with ELF[40] and QTAIM (quantum theory of atoms in
molecules)[41] have been reported. Structural representations
were generated using CYLView.[42] Animation given in the
supporting material was created by extracting and processing all
points of the IRC with an in-house program and saving the
corresponding images to create an animated GIF. The lithium
enolate derived from methyl acetate (ENa, Z = OMe), the actual
reagent employed in previous experimental reports,[20c, 43] was
FULL PAPER Postprint de EurJOC 2015, 4143-4152
used in the calculations. For the purpose of comparison and in
order to study the only differences exerted by diverse groups
vicinal to the carbonyl function, the corresponding enolates
derived from acetone (ENb, Z = Me) and acetaldehyde (ENc, Z
= H) were chosen as models. To reduce computational cost, the
model nitrone NI maintaining the fundamental characters of a
real N-substituted (Z)-nitrone (the preferred configuration for
aldonitrones), has been chosen.
Results and Discussion
Mechanistic study. Even though a lithium enolate can be
expressed as ROLi, its composition in a real solution is far more
complex. In polar solvents like THF (and in the absence of
chelating agents) lithium enolates are cubic tetramers,[44]
although in some cases dimers can be formed and, in the
presence of additives, monomers can also be present.[45] A
computational study carried out with the lithium enolate derived
from acetaldehyde demonstrated that monomeric species is
important in the equilibrium due to its high solvation energies,[46]
although more recent calculations showed that tetramer is the
major species in THF, monomeric species being preferred in the
presence of chelating agents.[47] Additional computational
studies reported that modeling by coordination to dimethyl ether
and dielectric solvation reduces considerably the exothermicity
of the aggregation.[48] An experimental study with the lithium
enolate of α-phenylcyclohexanone demonstrated that an
equilibrium exists between the monomer and the dimer, the
former being more reactive in alkylation reactions.[49] Thus, it is
reasonable to assume that, with independence of the structural
type of the lithium enolate in solution, the nitrone can break the
aggregates (in a similar way to the reactions with Grignard
reagents[50]) and form an initial complex SC as considered for
other reactions.[48]
We consider six different approaches, leading to the
corresponding transition structures, between nitrone NI and
monomeric enolates ENa, ENb and ENc, corresponding to three
staggered orientations and two different faces of the enolate
(Scheme 3). From these six approaches only three of them,
leading to a, b, and c series allow the preferred coordination of
both reagents to the lithium atom. Thus, for those leading to d, e,
and f series, corresponding to a direct approach without
formation of an initial complex, an additional molecule of solvent
has been added to complete a fourfold coordination sphere for
lithium.[51]
We first revisited the mechanism of the nucleophilic addition
of α-methoxyenolate ENa to nitrone NI. In our previous report[19]
we considered IN (Scheme 2), formed from complex SC through
TS-B1, as the final product of the reaction. However, the
reaction can continue through two alternative diastereomeric
channels to form cyclic cis and trans products PR which evolve
to the isoxazolidin-2-one 4 observed experimentally (Scheme 4). [6a,20c,52]
Scheme 3. Approaches between nitrone NI and enolates ENa-c.
Formally, the reaction between NI and ENa to form P1a and
P1b can be considered a [3+2] cycloaddition. The analysis of the
potential energy surface showed the direct approach higher in
energy and thus the corresponding transition structures TS1d,
TS1e and TS1f were not further considered (Figure 1). On the
other hand, formation of a complex C1 resulted in a stabilization
of 4.2 kcal/mol. Starting from C1 the three transition states TS1a,
TS1b and TS1c, corresponding to the formation of a C-C bond
between the most nucleophile center of the enolate ENa (the
unsubstituted methylene) and the most electrophilic center of the
nitrone NI (the azomethine carbon) through the two faces of the
enolate, were located. The complete mechanism is given in
Scheme 4 while the energy profile for the reaction and main
geometrical features of stationary points corresponding to the
formation of P1a and P1b are given in Figure 1.
The IRC analyses confirmed C1 as the starting point for
the three transition structures, and IN1b as the final point for
both TS1b and TS1c; for TS1a in which the addition of the
nitrone takes place by the other face of the enolate IN1a was
identified as the final point. The most stable transition state
corresponds to TS1a with an energy barrier of 6.4 kcal/mol
whereas TS1b and TS1c present barriers of 7.2 and 8.5
kcal/mol, respectively. According to a classical Boltzmann
distribution analysis, TS1a accounts for 80% of all the transition
structures but in terms of the mechanism it is irrelevant because
all the approaches are stepwise.
.
FULL PAPER Postprint de EurJOC 2015, 4143-4152
Scheme 4. Reaction betweeen nitrone NI and α-methoxy enolate ENa
Figure 1. Energy diagram (M06-2X/cc-pVTZ/PCM=THF) and stationary points for the reaction betweeen nitrone NI and α-methoxy enolate ENa. Relative free
energy values (ΔG298) are given in kcal/mol.
The distances of the forming bond in TS1a, TS1b and TS1c are
2.18, 2.14 and 2.15 Å, respectively, whereas the distances
between the nitrone oxygen and the enolate carbon linked to the
two oxygen atoms are 3.43, 3.11 and 3.54 Å for TS1a, TS1b
and TS1c, respectively thus confirming the absence of a close
interaction between the two reactive centers. Consequently, the
reaction is a typical nucleophilic addition. Indeed, any attempt of
locating concerted transition structures in which the formation of
the two bonds could take place in a concerted (although
asynchronous) manner, failed. The stability of IN1a and IN1b
was confirmed after the corresponding optimizations which
showed them to be 11.8 and 13.2 kcal/mol below the ground
state, respectively. Both intermediates could also interconvert
through a process of decoordination of the lithium atom and
rotation of the ester moiety. The formation of IN1a and IN1b is
followed by the intramolecular attack of the hydroxyamino group
TS1a TS1b TS1c TS4a TS4b
N-C-C-C: 65.3 N-C-C-C: 29.7 N-C-C-C: -31.6
FULL PAPER Postprint de EurJOC 2015, 4143-4152
to the ester carbonyl, via the planar four-membered ring
transition states TS4a and TS4b, leading eventually to the
lithium coordinated orthoesters P1a and P1b, respectively. The
forming C-O bond lengths in TS4a and TS4b are 2.06 Å and
1.94 Å, respectively and in both cases the IRC analysis showed
IN1a and IN1b as the starting points. Also, in both TS4a and
TS4b the forming isoxazolidine ring adopts an envelope
conformation. The channel b is favored over the channel a since
the nucleophilic attack of the oxygen atom to the ester carbonyl
in the latter is found to be sterically better positioned.
The whole processes are exergonic by 10.6 kcal/mol for
channel a and 14.5 kcal/mol for channel b. As a result, whereas
channel a is kinetically preferred because TS1a, at the rate-
determining step, is the most stable, channel b is more favorable
thermodinamically. However, the selectivity cannot be
experimentally observed because after quenching the reaction
the corresponding orthoesters eliminate the methoxy group to
give isoxazolidine-2-one 4. We have not studied computationally
the final step leading to 4 because it has no relevance in the
mechanism of the addition reaction. Thus, in the case of α-
methoxyenolates the stability of intermediates IN1a and IN1b is
ultimately responsible for the process to be stepwise. Indeed, in
some similar cases it has been observed experimentally[53] the
obtention of free hydroxylamine directly derived from those
complexes.
In the case of ketone enolate ENb, calculations also
establish that the direct approach, in which only ENb is
coordinated to lithium, are prohibitively high in energy, with
energy barriers of 30.2, 24.4 and 29.8 kcal/mol for TS2d, TS2e
and TS2f, respectively. On the other hand, starting from
complex C2, located at 4.2 kcal/mol below the ground state,
energy barriers of 8.3, 9.9 and 11.7 kcal/mol were found for
TS2a, TS2c and TS2b, respectively (Scheme 5, Figure 2). The
geometrical features as well as the energy profile are given in
Figure 2.
The IRC analysis for TS2a and TS2c (both attacking by the
same face of the enolate) confirmed intermediates IN2a and
IN2b as the final points of the reaction. However, the same
analysis for TS2b (corresponding to the attack for a different
face of the enolate) indicated the process as concerted, the
product P2a being the final point. The geometries of transition
structures TS2a-c (R = Me, Scheme 5) are similar to the
corresponding partners TS1a-c (Scheme 4) but the electronic
features are different. In the case of TS1b, the presence of the
methoxy group contributes to stabilize the developing partial
positive charge at the carbonyl carbon atom; the C-O distance of
3.11 Å indicates that electrostatic interaction is not enough for
causing the collapse of the second forming bond. Under these
circumstances the intermediate IN1b is enough stable to exist.
On the other hand, in TS2b the methyl group is not capable of
stabilizing the above mentioned partial positive charge and,
consequently, the electrostatic interaction between carbon and
oxygen atoms is stronger (as revealed by a shorter C-O distance
of 3.05 Å). In this scenario the C-O interaction collapses to a
bond and the reaction takes place in one single kinetic step. This
sort of spontaneous downhill process is well known and it has
also been observed by other authors.[54] The endo orientation of
the methyl group causes unfavorable steric interactions that
explain the higher energy of TS2b with respect to TS2a and
TS2c. As in the case of α-methoxyenolate, the formation of IN2a
and IN2b is followed by an intramolecular attack through TS5a
and TS5b leading to orthoesters P2a and P2b, respectively
(Scheme 5, R = Me).
Scheme 5. Reaction betweeen nitrone NI and enolates ENb,c
.
FULL PAPER Postprint de EurJOC 2015, 4143-4152
Figure 2. Energy diagram (M06-2X/cc-pVTZ/PCM=THF) and stationary points
for the reaction betweeen nitrone NI and α-methoxy enolate ENb. Relative free
energy values (ΔG298) are given in kcal/mol.
Notably, the IRC analysis of the concerted pathway showed a
shoulder revealing the presence of a so-called hidden
intermediate (Figure 3).[55] According to this analysis and the
excessively long forming C-O bond (3.05 Å), only when the
transition state is passed and the C-C bond is formed, does the
formation of the second C-O bond start. This process consisting
in two consecutive chemical events (formation of C-C and C-O
bonds) is in agreement with a typical one-step-two-stages
reaction according to Domingo and co-workers[39b] and similar to
that observed for the reaction between nitrones and lithium
ynolates.[27b] Indeed, on going from TS2b to cycloadduct P2b,
through IRC, intermediate structures (see below the ELF
analysis) have the C-C bond already formed whereas the C-O
bond formation is very delayed. However, steric reasons due to
the inside orientation of the methyl group make TS2b higher in
energy and we can conclude that this path is not preferred for
this reaction. The Boltzmann distribution analysis predicted that
TS2a, corresponding to the stepwise process, accounts for
almost 95% of all the transition structures while TS2b,
corresponding to the one-step process, accounts for only 5%.
Consequently, despite the presence of the concerted path, the
reaction between nitrone NI and α-methyl enolate ENb takes
place through a stepwise mechanism with a barrier of 8.3
kcal/mol at the rate-limiting step.
Figure 3. Computed (M06-2X/cc-pVTZ/PCM=THF) backwards intrinsic
reaction coordinate (IRC) for the reaction between nitrone NI and enolate ENb
showing the relative energy (top) and the gradient norm showing a prominent
hidden intermediate (bottom).
A similar situation accounts in the reaction between nitrone NI
and enolate ENc. Again, the three transition structures
corresponding to the direct approach present very high energy
barriers (30.8, 27.9 and 29. 2 kcal/mol for TS3d, TS3e and TS3f,
respectively). The free energy barriers for lithium-coordinated
transition structures TS3a, TS3b and TS3c are calculated to be
12.3, 10.5 and 12.1 kcal/mol, respectively. The geometrical
features as well as the energy profile are given in Figure 4.
As observed for α-methyl enolate, TS3b appeared as a
highly asynchronous transition structure with a long C-O forming
bond (2.99 Å) in comparison with the C-C forming bond (2.10 Å).
The IRC calculation confirmed the concertedness of the reaction
revealing no intermediates between TS3b and P3b. However,
contrary to α-methyl enolate, transition state TS3b,
TS2a TS2bTS2c
TS5a TS5b
N-C-C-C: 75.7 N-C-C-C: 43.9N-C-C-C: -45.7
hidden
intermediate
TS2b
P2a
C2
FULL PAPER Postprint de EurJOC 2015, 4143-4152
corresponding to the one-step process, showed to be the most
stable (by 1.6 kcal/mol) confirming a change of mechanism from
enolate ENb to enolate ENc. In fact, the Boltzmann distribution
analysis indicated in this case that TS3b accounts for almost
92% of all the transition structures while TS3a and TS3c,
corresponding to stepwise processes, account for ca. 3% and
5%, respectively. The steric contact of the N-methyl group is
more unfavorable for the methyl group (TS2b) than for the
hydrogen atom (TS3b), thus predicting a lower barrier for the α-
unsubstituted enolate ENc (Figure 4). The unfavorable formation
of IN3a and IN3b is followed by an intramolecular attack through
TS6a and TS6b leading to orthoesters P3a and P3b,
respectively (Scheme 5, R = H). The IRC calculation for the
concerted process show similar features to those observed in
the case of α-methyl enolate for TS2b. It confirms that C3 and
P3a are connected by TS3b without intermediates but a hidden
intermediate is also present (Figure 5). Thus, in the case of the
α-unsusbstituted enolate ENc, the reaction takes place
preferentially along a concerted two-stage one-step mechanism
with an energy barrier of 10.5 kcal/mol.
Figure 4. Energy diagram (M06-2X/cc-pVTZ/PCM=THF) and stationary points
for the reaction betweeen nitrone NI and α-methoxy enolate ENc. Relative free
energy values (ΔG298) are given in kcal/mol.
Figure 5. Computed (M06-2X/cc-pVTZ/PCM=THF) intrinsic reaction
coordinate (IRC) for the reaction between nitrone NI and enolate ENc showing
the relative energy (top) and the gradient norm showing a prominent hidden
intermediate (bottom).
NCI and ELF analyses. The topological analysis of ELF has
recently demonstrated to be of great utility in analyzing C-C
bond formation in a variety of non-polar, polar and ionic organic
reactions.[56] The NCI analysis[33] has also demonstrated their
utility in the analysis of several reactions[55b,57] including
nucleophilic additions to C=N bonds.[58] We have carried out the
complete ELF and NCI analyses for the IRCs corresponding to
the most stable paths of the addition reactions of enolates ENa-
c to nitrone NI (For animations showing movies of the reactions
illustrating both ELF and NCI analyses see supporting material).
The numbering used for the analyses is illustrated in Figure 6.
ELF basin populations of selected points on the IRC including
initial and final points, transition structures, intermediates and
points indicating bond formation are given in the supporting
information.
TS3a TS3bTS3c
TS6a TS6b
N-C-C-C: 45N-C-C-C: -44.7N-C-C-C: 101.0
hidden
intermediate
TS3b
P3aC32
FULL PAPER Postprint de EurJOC 2015, 4143-4152
Figure 6. Numbering used for ELF and NCI analyses.
In the case of the reaction between NI and ENa leading to TS1,
the double C3=N1 bond is transformed into the single C3-N1
bond, the double C6=C7 bond is transformed into the single C6-
C7 bond and the C3-C7 bond is created. The ELF descriptors
corresponding to this step are presented in Figure 7. The two
disynaptic basins associated to the C3=N1 and C6=C7 double
bonds are merged, in TS1a (point 58 of the IRC), each other to
become one indicating the transformation of the doble bonds
into single one; in fact the electronic populations decreased
slightly for both C3-N1 and C6-C7 bonds. The decreasing of the
electronic population of C3-N1 and C6-C7 bonds continues
during C3-C7 bond formation (points 55 and 54 of the first IRC)
and simultaneously a monosynaptic basin appeared at C7. At
point 55 (d(C3,C7) = 2.04 Å; d(C6,O2) = 3.45 Å) two
monosynaptic basins, V(C3) and V(C7), appeared at the
reacting centers. These basins are associated to the two centers
responsible for the subsequent bond formation. Indeed, at the
next point on the IRC (point 54) they have merged into a new
disynaptic basin, V(C3,C7) confirming the C3-C7 bond formation.
Figure 7. Most relevant ELF attractors at selected points of the backwards
IRCs of the stepwise reaction between nitrone NI and enolate ENa..
In the second step of the reaction, at TS4a (point 28 of the
IRC) no monosynaptic basins appeared at the centers
responsible of the formation of the second bond, C6 and O2. It is
at point 21 when two monosynaptic basins, V(C6) and V(O2),
appeared. At P20 they have merged into a disynaptic one
confirming the formation of the new bond
The NCI analysis (Figure 8) for this reaction corroborates
and complements the data observed during the ELF analysis.
The starting complex, C1, shows a typical attractive interaction
(green surface) between the π systems corresponding to
electron-rich enolate C=C bond and the electron-poor nitrone
C=N bond. At the intermediate IN1a a clear non-covalent
interaction is observed between C6 and O2 (blue surface) in
agreement with a relatively short distance of 2.70 Å and despite
the formation of the second C6-O2 bond does not have started,
as mentioned above. This observation is in agreement with that
made for anionic stepwise [3+2] cycloadditions by Schelyer and
co-workers who considered this sort of interaction as strictly
electrostatic.[59] More recently, we have also observed the same
type of interactions in the stepwise cycloaddition between
nitrone ylides and alkenes.[20b] For transition structures TS1a and
TS4a the incipient formation of the new bonds is evidenced by
the typical toroidal blue surfaces (Figure 8). At TS1a is evident
that the interaction between C6 and O2 is negligible only being
appreciable at the following stationary point IN1a.
Figure 8. NCI analysis of relevant points C1, IN1a, TS1a and TS4a
corresponding to the stepwise reaction between nitrone NI and enolate ENa..
For the concerted reaction between nitrone NI and enolate ENc
the attractor positions for points indicating bond formation are
illustrated in Figure 9. For this reaction the ELF analysis of the
attractors for C3 shows, in a similar way to C1, two disynaptic
basins associated each one to the C3=N1 and C6=C7 double
bonds of the nitrone and enolate moieties, respectively. At TS3b
(point 60 of the IRC) the C6-C7 and C3-N1 bonding regions are
characterized by V1(C6,C7) and V1(C3,N1) disynaptic basins,
which showed loss of electron density associated to the creation
of the new C3-C7 bond. A monosynaptic basin V(C7) is
observed and at P62 a new monosynaptic basin, V(C3), appears
P55 P54
P21 P20
V(C7)
V(C3)
V(C6)
V(O2)
V(C3,C7)
V(C6,O2)
C1 IN1a
TS1a TS4a
C7
C7
C6
C6
C7
C6
C6
C7
C3
C3C3
C3
O2
O2
O2O2
FULL PAPER Postprint de EurJOC 2015, 4143-4152
and the electron density of V(C7) increases. At the following
point, P63, the two monosynaptic basins V(C3) and V(C7) have
merged into a new disynaptic basin V(C3,C7). Notably, P62 and
P63 associated with the first stage of the concerted process
have similar electronic structures to P55 and P54 associated
with the stepwise addition of ENa (see above). This indicates a
similar arrangement in the formation of the first C-C bond,
independently of the appearance of a further intermediate,
whose stability (or existence) depends on electronic features
that could stabilize such stationary point. Indeed, P63 resembles
geometrically IN1a and the absence of V(C6,O2) attractor
confirms that formation of the second bond has not begun. At
P96 both C3,C7 distance (1.54 Å) and the presence of V(C3,C7)
attractor indicate the complete formation of the C3-C7 bond. At
the same time, two monosynaptic basins, V(C6) and V(O2)
appear. These basins merge, at P97, into a new disynaptic
basin (VC6,O2) responsible of the formation of the second bond.
Figure 9. Most relevant ELF attractors at selected points of the IRCs of the
concerted reaction between nitrone NI and enolate ENc..
The NCI analysis of the starting complex C3, the transition
structure TS3b and the two points, P63 and P97, in which the
formation of the bonds has just taken place is illustrated in
Figure 10. Similarly to C1, complex C3 shows an attractive
interaction (green surface) between the π systems
corresponding to electron-rich enolate C=C bond and the
electron-poor nitrone C=N bond. TS3b shows the interaction
corresponding to the forming bond (toroidal blue surface). TS3b
and P63 are very similar in their geometrical structure and both
show a slight attractive interaction between C6 and O2 in a
similar way (although weaker) to that observed for IN1 in the
stepwise addition of ENa. Although an intermediate is not
formed it is evident that the second bond (C6-O2) is not formed
at this stage of the reaction, being completely formed only at
P97.
The case of the reaction between nitrone NI and α-methyl
enolate ENb can be considered as an intermediate situation
which, however, opts by a stepwise mechanism due to
unfavourable steric interactions still present between the methyl
group of the α-enolate and the N-methyl group. Both the ELF
and NCI analyses are rather similar to those discussed above
for the reaction with enolate ENa by just replacing the α-methoxy
group by the α-methyl group. The same applies for the non-
preferred concerted path which is rather similar to those found
for enolate ENc by just replacing the α-methyl group by an
hydrogen atom (For the complete analyses of both concerted
and stepwise pathways of the reaction between nitrone NI and
enolate ENb see supporting information).
Figure 10. NCI analysis of relevant points C3, TS3a, P63 and P97
corresponding to the concerted reaction between nitrone NI and enolate ENc.
Conclusions
The addition of lithium enolates to nitrones takes place through
the initial coordination of the nitrone to the lithium atom. Then,
the intramolecular attack of the enolate moiety to the nitrone
from initial complexes can take place by two different faces of
the enolate. This causes that the α-substituent of the enolate
(OMe, Me or H) can adopt inside and outside orientations with
respect to the nitrone (Figure 11).
Figure 11. Preferred approaches and change of mechanism for enolates
derived from esters and ketones (Z= OMe, Me), and aldehydes (Z=H).
(dashed lines indicate forming bonds).
P63 P63
P96 P97
V(C7)
V(C3)V(C3,C7)
V(C6)
V(C2)V(C6,O2)
C3 TS3b
P63 P97
C7
C6
C3O2
C6
C6C6
C7C7
C7
C3 C3
C3O2
O2
O2
FULL PAPER Postprint de EurJOC 2015, 4143-4152
The inside position is sterically more demanding because of
unfavorable interactions with the N-methyl group of the nitrone
and thus, the outside orientation is preferred. However, this
approach involves a large separation between C and O atoms
responsible of the formation of the second C-O bond. This
excessively long C-O distance, minimizing attractive electrostatic
interactions, avoids bonding between the interacting orbitals at
the TS, and when an electron-donor substituent (OMe) is
present the reaction is stepwise because of the electronic
stabilization of the intermediate (addition of ENa). In the
absence of α-substituent the inside orientation is preferred
(shortening the C-O distance) and the reaction change its
mechanism to concerted through a highly asynchronous
transition structure (addition of ENc). The reaction with the α-
methyl enolate (ENb) represents an intermediate situation in
which there is a substituent stabilizing in less extent the
intermediate but still causing unfavorable steric interactions.
Consequently, the concerted path appeared but is not the
preferred one and the stepwise pathway shows a higher barrier
(8.3 kcal/mol) than in the case of α-methoxy enolate (6.4
kcal/mol).
The one-step processes are so asynchronous that they are
more in agreement with a reaction which takes place in one
single kinetic step but in two stages. This concept has been
introduced by Domingo and co-workers[60] and it is evidenced
from the ELF analyses of the corresponding IRC calculations.
From these analyses of the changes of bonding along the
reaction coordinate we can conclude that, in the one-step
processes, the formation of the second C-O bond only begins
when the first C-C bond is completely formed. Consequently,
these concerted highly asynchronous reactions do not follow a
typical cyclic electron-reorganization as supported by the
presence of hidden intermediates in the corresponding IRCs. As
predicted by Rzepa and co-workers,[55b] stereoelectronic
influence on the geometry induces the system to form a real
intermediate.
In summary, while the reaction with α-unsusbtituted enolate
ENc takes place along a one-step two-stage mechanism, the
presence of a substituent at the α-position in enolate (ENa and
ENb) able to both lengthen the C-O distance -avoiding orbital
interactions- and stabilize the corresponding intermediate,
switches the mechanism to a stepwise process.
Acknowledgements
This work was supported by the Ministerio de Economía y
Competitividad (MINECO) and FEDER Program (Madrid, Spain,
project CTQ2013-44367-C2-1-P) and the Gobierno de Aragón
(Zaragoza, Spain. Bioorganic Chemistry Group. E-10). We
acknowledge the Institute of Biocomputation and Physics of
Complex Systems (BIFI) at the University of Zaragoza for
computer time at clusters Terminus and Memento. D.R.-L.
thanks the Spanish Ministry of Education (MEC) for a pre-
doctoral grant (FPU program)..
Keywords: Mannich reaction • Nitrones • Enolates • NCI
analysis • ELF analysis
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Depending on the type of enolate the reaction mechanism changes from one-step
to stepwise
D. Roca-Lopez, V. Polo, T. Tejero and
P. Merino*
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Title